A large Rab GTPase encoded by
 CRACR2A
 
 is a component of subsynaptic vesicles that transmit T cell activation signals

Srikanth, Sonal; Kim, Kyun-Do; Gao, Yuanyuan; Woo, Jin Seok; Ghosh, Shubhamoy; Calmettes, Guillaume; Paz, Adrian; Abramson, Jeff; Jiang, Meisheng; Gwack, Yousang

doi:10.1126/scisignal.aac9171

Cited by 32 publications

(80 citation statements)

References 41 publications

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“…and (2) their localization to a small, perinuclear compartment at the cell center, suggestive of microtubule minus-end-directed transport (Srikanth et al, 2016;Shintani et al, 2007). The human CRACR2a gene was shown to undergo alternative splicing to produce two isoforms (Srikanth et al, 2016;Wilson et al, 2015). In this study, we focused on the long isoform, as the short isoform lacks the Rab GTPase domain and does not seem to be involved in membrane trafficking (Srikanth et al, 2016).…”

Section: Identification Of Rab45 and Cracr2a As Activating Adaptors Fmentioning

confidence: 99%

“…The human CRACR2a gene was shown to undergo alternative splicing to produce two isoforms (Srikanth et al, 2016;Wilson et al, 2015). In this study, we focused on the long isoform, as the short isoform lacks the Rab GTPase domain and does not seem to be involved in membrane trafficking (Srikanth et al, 2016).…”

Section: Identification Of Rab45 and Cracr2a As Activating Adaptors Fmentioning

confidence: 99%

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A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

Wang

Huynh

et al. 2018

Preprint

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Cytoplasmic dynein is a microtubule minus-end-directed motor that transports numerous intracellular cargoes. Mammalian dynein transport is initiated by coiled-coil adaptor proteins that 1) join dynein and its co-factor dynactin into a complex capable of processive motility, and 2) interact with a cargo-bound receptor, which is frequently a Rab GTPase on an organelle. Here, we report two novel dynein adaptors, CRACR2a and Rab45, which have a coiled-coil adaptor domain, a pair of EF hands, and a Rab GTPase domain fused into a single polypeptide. We find that CRACR2a-mediated dynein-dynactin motility is activated by calcium in vitro and in cells. In activated T cells, CRACR2a localizes to clathrin-independent endosomes that require microtubule-based transport to detach from the actin cortex and travel towards the microtubule organizing center. Together these results represent the first known examples of Rab GTPases that directly act as dynein adaptors and implicate CRACR2a-dynein in regulation of endocytic trafficking in T cells. Condensed title: A calcium-regulated dynein adaptor in T cells

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Section: Identification Of Rab45 and Cracr2a As Activating Adaptors Fmentioning

confidence: 99%

Section: Identification Of Rab45 and Cracr2a As Activating Adaptors Fmentioning

confidence: 99%

A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

Wang

Huynh

et al. 2018

Preprint

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“…Our recent work (detailed below) emphasizes the role of CRACR2A contained in vesicles, which are independent from Latcontaining vesicles, in activation of the Ca 2C -NFAT and Jnk-AP1signaling pathways. 18 Together, the results from studies on the roles of Lat and CRACR2A suggest that TCR signaling events are not restricted to the plasma membrane, but they also involve additional steps of vesicle trafficking that carries signaling molecules from the intracellular pool to the immunological synapse.…”

mentioning

confidence: 96%

“…19 Recent work validated presence of the long isoform CRACR2A-a in both human and murine tissues (and cells), particularly, in lymphoid organs. 18,20 Both these isoforms share conserved function in activation of the Ca 2C -NFAT pathway, but only CRACR2A-a has a unique role in activation of the Jnk MAPK pathway, emphasizing the importance of the additional prolinerich and Rab GTPase domains in these events. CRA-CR2A-a contains N-terminal EF hands and a coiled coil domain, which are conserved with CRACR2A-c. A proline-rich domain and C-terminal Rab GTPase domain are uniquely present in CRACR2A-a.…”

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confidence: 99%

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A large Rab GTPase family in a small GTPase world

2016

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More than 60 Rab GTPases exist in the human genome to regulate vesicle trafficking between organelles. Rab GTPases are members of the Ras GTPase superfamily that broadly control budding, uncoating, motility and fusion of vesicles in most cell types. Rab proteins interconvert between active, GTP-bound form and inactive, GDP-bound form. In their active conformation, they interact with various effector molecules to carry out diverse functions. Rab GTPases are usually small containing only a GTPase domain with a C-terminal prenylation site for membrane anchoring. Recently, we identified a large G protein, CRACR2A (CRAC channel regulator 2A), which uncovers novel functions of Rab GTPases. First, CRACR2A encodes a large Rab GTPase containing multiple functional domains contrary to small Rab GTPases. Second, CRACR2A plays an unexpected role in regulating intracellular signaling pathways important for T cell activation, unlike the canonical role of small Rab GTPases. Vesicles containing CRACR2A bud out from the proximal Golgi area and translocate into the immunological synapse to activate these signaling pathways. Third, instead of recycling, CRACR2A is consumed by a unidirectional pathway. These events are sequentially regulated by prenylation, GTP binding, protein interaction with a signaling adaptor Vav1, and degradation. Together, our findings reveal a novel function of a large Rab GTPase in intracellular signaling pathways, which may be shared by other large Rab GTPases, Rab44 and Rab45.

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Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes

Srikanth

Woo

Sun

et al. 2017

Store-Operated Ca²⁺ Entry (SOCE) Pathways

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Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway. Stimulation of TCRs triggers depletion of intracellular Ca store and, in turn, activates store-operated Ca entry (SOCE) to raise the intracellular Ca concentration. SOCE in T cells is mediated by the Ca release-activated Ca (CRAC) channels, which have been very well characterized in terms of their electrophysiological properties. Identification of STIM1 as a sensor to detect depletion of the endoplasmic reticulum (ER) Ca store and Orai1 as the pore subunit of CRAC channels has dramatically advanced our understanding of the regulatory mechanism of Ca signaling in T cells. In this review, we discuss our current understanding of Ca signaling in T cells with specific focus on the mechanism of CRAC channel activation and regulation via protein interactions. In addition, we will discuss the role of CRAC channels in effector T cells, based on the analyses of genetically modified animal models.

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A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals

Cited by 32 publications

References 41 publications

A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

A new calcium-activated dynein adaptor protein, CRACR2a, regulates clathrin-independent endocytic traffic in T cells

A large Rab GTPase family in a small GTPase world

Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes

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